It is well known that
the cytochrome P-450 (CYP) enzyme system is involved in the drug metabolism of
many medications used in clinical practice and have been implicated in causing
clinically relevant drug-drug interactions.1,2 There are a number of
CYP450 enzymes involved in mediating drug interactions and commonly include
CYP1A2, 2C9, 2C19, 2D6, and 3A4.1 Of these CYP enzymes, CYP3A4 is not
only the most prevalent CYP enzyme in the liver, but is used by more than 50%
of medications on the market for their metabolism and elimination from the
body.1 The problem occurs when in the metabolism of these substrates
of CYP3A4 also result in the inhibition of CYP3A4. A number of
medications are known to be inhibitors of CYP3A4, but they differ in the degree
of inhibition they have on the enzyme and the type of inhibition they confer.1
One type of inhibition of CYP3A4 is mechanism-based inhibition.3
Mechanism-based
inhibition typically results in the irreversible inhibition of CYP3A4, thereby
making that enzyme completely nonfunctional until it is replaced with newly
synthesized CYP3A4 enzymes.3 The irreversible inhibition of CYP3A4 occurs
during the metabolism of the inhibitor itself. The medication causing the
inhibition of CYP3A4 is also a substrate of CYP3A4 for its metabolism.
The irreversible inhibition of CYP3A4 occurs in the middle of metabolizing the
medication known to be a mechanism-based inhibitor because of the formation of
a metabolite intermediate.4 These metabolic intermediates can then
form covalent bonds with CYP3A4, thereby resulting in the irreversible
inhibition of their activity. Medications known to commonly cause this
type of inhibition to CYP3A4 are commonly characterized as having the following
moieties associated with the chemical structure: tertiary amine function, furan
rings, and acetylene function.3,5-7
Due
to the irreversible inhibition of CYP3A4, and knowing the large number of
medications known to depend on this enzyme for their metabolism, the
medications known to cause this are associated with clinically relevant
drug-drug interactions. Examples of medications that are known to be
mechanism-based inhibitors include: clarithromycin, delavirdine, diltiazem,
erythromycin, and verapamil.3 Understanding the underlying
mechanism for this type of inhibition of CYP3A4 can help the clinician to
appropriately assess, monitor and avoid drug interactions that would compromise
the safety of their patients.
References:
- Rendic S, Ci Carlo FJ. Human cytochrome P450 enzymes: a status
report summarizing their reactions, substrates, inducers, and
inhibitors. Drug Metab Rev 1997;29:413-580.
- United
States Food and Drug Administration. Guidance for Industry. Drug
Interaction Studies - Study Design, Data Analysis, and Implications for
Dosing and Labeling. September 2006. Clinical Pharmacology. Accessed
last on 5/19/2009.
- Zhou
S, Yung Chan S, Cher Goh B et al. Mechanism-based inhibition of
cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet
2005;44:279-304.
- Kent
UM, Juschyshyn MI, Holenberg PF. Mechanism-based inactivators as
probes of cytochrome P450 structure and function. Curr Drug Metab
2001;2:215-43.
- Larrey
D, Funck-Brentano C, Breil P et al. Effects of erythromycin on hepatic
drug-metabolizing enzymes in humans. Biochem Pharmacol
1983;32:1063-8.
- He
K, Iyer KR, Hayes RN et al. Inactivation of cytochrome P450 3A4 by
bergamottin, a component of grapefruit juice. Chem Res Toxicol
1998;11:252-9.
- Guengerich
FP. Mechanism-based inactivation of human liver microsomal cytochrome
P-450 IIIA4 by gestodene. Chem Res Toxicol 1990:3:363-71.